(Stroke. 2000;31:526.)
© 2000 American Heart Association, Inc.
Original Contributions |
Mechanism of Endothelin-1–Induced Contraction in Rabbit Basilar Artery
From the Department of Neurosurgery, University of Mississippi Medical Center, Jackson.
Correspondence to John Zhang, MD, PhD, Department of Neurosurgery, University Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505. E-mail jzhang{at}neurosurgery.umsmed.edu
Background and Purpose—Endothelin-1 (ET-1) is suggested to be a major cause of cerebral vasospasm after subarachnoid hemorrhage. However, the mechanism of ET-1–induced contraction in cerebral arteries remains unclear. This study was undertaken to demonstrate the possible role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in ET-1–induced contraction.
Methods—PD-98059, damnacanthal, wortmannin, AG-490, genistein, calphostin C, and staurosporine were used to inhibit, or relax, the ET-1–induced contraction of basilar artery, studied with an isometric tension system. Immunoprecipitation of MAPK in ET-1–stimultated rings of basilar artery without or with the above inhibitors was studied with Western blot.
Results—(1) ET-1 produced concentration-dependent contraction and MAPK immunoprecipitation in rabbit basilar artery by activation of ETA but not ETB receptors. (2) MAPK inhibitors PD-98059 and U-0126 produced dose-dependent inhibition of ET-1–induced contraction. (3) The Src tyrosine kinase inhibitor damnacanthal, the phosphatidylinositol-3 kinase inhibitor wortmannin, and the Janus tyrosine kinase2 inhibitor AG-490 abolished ET-1–induced contraction. (4) The PKC inhibitor staurosporine but not calphostin C abolished ET-1–induced contraction, and the PTK inhibitor genistein partially reduced ET-1–induced contraction. (5) In arteries precontracted by ET-1, PD-98059, U-0126, wortmannin, AG-490, genistein, and staurosporine produced concentration-dependent relaxation. (6) ET-1 induced a biphasic and time-dependent MAPK immunoprecipitation. (7) PD-98059, U-0126, genistein, AG-490, and damnacanthal, but not staurosporine or wortmannin, abolished the effect of ET-1 on MAPK immunoreactivity.
Conclusions—This study demonstrated that MAPK may be involved in ET-1–induced contraction in rabbit basilar artery. MAPK is downstream of PTK, Src, and Janus tyrosine kinase pathways but may not be downstream of phosphatidylinositol-3 kinase pathways. The possible involvement of PKC in ET-1–induced contraction requires further investigation. Inhibition of these pathways may offer alternative treatment for ET-1–induced contraction and cerebral vasospasm.
Editorial Comment
Department of Anesthesiology, Baylor College of Medicine, Houston, Texas
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